hepatorenal syndrome the 8th international consensus conference 2012

7/28/2019 Hepatorenal Syndrome the 8th International Consensus Conference 2012

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R E S E A R C H Open Access

Hepatorenal syndrome: the 8th internationalconsensus conference of the Acute DialysisQuality Initiative (ADQI) GroupMitra K Nadim1*, John A Kellum2, Andrew Davenport3, Florence Wong4, Connie Davis5, Neesh Pannu6,

Ashita Tolwani7, Rinaldo Bellomo8 and Yuri S Genyk9, for The ADQI Workgroup

Abstract

Introduction: Renal dysfunction is a common complication in patients with end-stage cirrhosis. Since the original

publication of the definition and diagnostic criteria for the hepatorenal syndrome (HRS), there have been majoradvances in our understanding of its pathogenesis. The prognosis of patients with cirrhosis who develop HRS

remains poor, with a median survival without liver transplantation of less than six months. However, a number of

pharmacological and other therapeutic strategies have now become available which offer the ability to prevent or

treat renal dysfunction more effectively in this setting. Accordingly, we sought to review the available evidence,

make recommendations and delineate key questions for future studies.

Methods: We undertook a systematic review of the literature using Medline, PubMed and Web of Science, data

provided by the Scientific Registry of Transplant Recipients and the bibliographies of key reviews. We determined a

list of key questions and convened a two-day consensus conference to develop summary statements via a series

of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated

recommendations and/or directions for future research.

Results: Of the 30 questions considered, we found inadequate evidence for the majority of questions and our

recommendations were mainly based on expert opinion. There was insufficient evidence to grade three questions,but we were able to develop a consensus definition for acute kidney injury in patients with cirrhosis and provide

consensus recommendations for future investigations to address key areas of uncertainty.

Conclusions: Despite a paucity of sufficiently powered prospectively randomized trials, we were able to establish

an evidence-based appraisal of this field and develop a set of consensus recommendations to standardize care and

direct further research for patients with cirrhosis and renal dysfunction.

Keywords: hepatorenal syndrome, cirrhosis, acute kidney injury, ADQI, RIFLE

IntroductionHepatorenal syndrome (HRS) is a unique form of kidney

injury resulting from renal vasoconstriction in the set-

ting of systemic and splanchnic arterial vasodilatation inpatients with advanced cirrhosis. HRS is typically subdi-

vided into two types: type-1 in which there is a rapid

deterioration in kidney function with the serum creati-

nine (Scr) increasing by more than 100% from baseline

to greater than 2.5 mg/dl within a two-week period,

whereas type-2 HRS occurs in patients with refractory

ascites with either a steady but moderate degree of func-

tional renal failure ( 1.5 mg/dl) or a deterioration inkidney function that does not fulfill the criteria for HRS

type-1 [1]. In patients with advanced cirrhosis, HRS is

reported to occur in 18% within one year of diagnosis

and up to 40% at five years [2]. Untreated, median survi-

val is two weeks for patients with type-1 HRS and four

to six months in patients with type-2 HRS [3]. However,

many patients with lesser degrees of renal impairment

in the setting of cirrhosis do not meet the precise

* Correspondence: [email protected] of Medicine, University of Southern California, 1520 San Pablo

Street, Suite 4300, Los Angeles, CA, 90033 USA

Full list of author information is available at the end of the article

Nadim et al. Critical Care 2012, 16:R23

http://ccforum.com/content/16/1/R23

2012 Nadim et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.
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definitions of HRS and, yet, have the same pathophysio-

logical basis to their renal impairment and, therefore,

could potentially benefit from therapies developed for

HRS. A consensus conference under the auspices of the

Acute Dialysis Quality Initiative (ADQI) was held in

2010. The purpose of this consensus conference was to

review the literature on renal impairment in cirrhosis

and to create the basis for a definition and classification

system of all forms of renal impairment including HRS,

from there to develop a broader understanding of its

epidemiology, review current knowledge in the field of

prevention and treatment, and develop the framework

for a research agenda in relation to this condition.

Material and methodsADQI process

ADQI is an ongoing process that seeks to produce evi-

dence-based recommendations for the prevention andmanagement of acute kidney injury (AKI) and on differ-

ent issues concerning acute dialysis. It represents a non-

profit association with an elected rotating board. ADQI

conducts systematic reviews of the literature and pro-

vides expert-based statements and interpretation of cur-

rent knowledge for use by clinicians according to

professional judgment. The ADQI methods comprise (1)

systemic search for evidence with review and evaluation

of the available literature, (2) establishment of clinical

and physiologic outcomes as well as measures to be

used for comparison of different treatments, (3) descrip-

tion of the current practice and the rationale for use of

current techniques, and (4) analysis of areas in which

evidence is lacking and future research is required.

Prior to the conference, the organizing committee of

ADQI VIII identified five topics relevant to the field of

HRS (Table 1). We selected these topics with a set of key

questions based on (1) prevalence of the associated clini-

cal problem, (2) known variation in clinical practice, (3)

availability of scientific evidence, (4) potential importance

for clinical outcome, and (5) development of evidence-

based medicine guidelines. For each topic, we outlined a

preliminary set of key questions. We then assembled a

diverse international panel representing multiple relevant

disciplines (nephrology, hepatology, transplant surgeryand critical care), from a variety of countries and scienti-

fic societies based on their expertise in AKI and HRS.

Panelists were assigned to four to five person work

groups, one of whom served as the group facilitator with

each work group addressing one key topic.

ADQI activities were divided into a pre-conference,

conference and post-conference phase. During the pre-

conference phase, topics were selected, and the work

groups were assembled and assigned to specific topics.

Each group identified a list of key questions, conducted

a systematic literature search and generated a bibliogra-

phy of key studies. During this stage, the scope of the

conference was also defined and some topics were

excluded (Table 1). We then conducted a 2 1/2 -day

conference. Our consensus process relied on evidence

where available and, in the absence of evidence, consen-

sus expert opinion where possible. The quality of the

overall evidence and the strength of recommendations

were graded using the Grading of Recommendations

Assessment, Development and Evaluation system (Table

2) [4-6]. For interventions that have been studied usingrandomized trials we pooled the results of various trials

using the Mantel-Haenszel method for calculating the

weighted summary odds ratio under the fixed effects

model. We also calculated the heterogeneity statistic

and incorporated it to calculate the summary odds ratio

under the random effects model [7,8]. Both fixed and

random effects models are reported.

During the conference, work groups assembled in

breakout sessions, as well as in plenary sessions where

their findings were presented, debated and refined. In

each breakout session, the work groups refined the key

questions, identified the supporting evidence, and gener-

ated practice recommendations and/or directions for

future research as appropriate. A series of summary

statements was then developed during the breakout ses-

sions and presented to the entire group, revising each

statement as needed until a final version was agreed

upon. Directives for future research were achieved by

asking the participants to identify deficiencies in the lit-

erature, determine if more evidence was necessary and if

so, to articulate general research questions. When possi-

ble, pertinent study design issues were also considered.

Final reports were summarized into a final conference

document by a writing committee.

Systematic review of the literature

For each topic, the systematic review included the devel-

opment of well specified research questions, literature

Table 1 Topics covered and excluded in the Consensus Conference

Topics Covered Topics Excluded

Evaluation of renal function in patients with cirrhosis Current definition and Classification of HRS Pharmacologic treatment of HRS Device management of HRS Surgical and interventional management of HRS

Indication for renal replacement initiation Determinants for patient selection for extracorporeal system Patient selection for liver transplantation Post transplant immunosuppresion management



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searches, data extraction of primary studies and existingsystematic reviews, tabulation of data, assessment of the

quality of individual studies, and assessment of the over-

all quality of the literature and summary conclusions.

Literature review was applied using key terms relevant

to the topic and electronic reference libraries with the

focus on human studies and limited to English language

articles published between January 1960 and December

2009. Study eligibility was based on population, inter-

vention, comparator, outcome, and study design relevant

to each clinical question. Although nonrandomized stu-

dies were reviewed, the majority of the Work Group

resources were devoted to review of randomized trials,

as these were deemed to be most likely to provide data

to support level 1 recommendations with very high- or

high-quality (A or B) evidence. Exceptions were made

for topics with sparse evidence. Each work group con-

ducted literature searches related to their topic ques-

tions via MEDLINE, PubMed, data provided by the

Scientific Registry of Transplant Recipients, Web of

Science and the bibliographies of key reviews and of all

articles that met the search criteria. Decisions to restrict

the topics were made to focus the systematic reviews on

those topics in which existing evidence was thought to

be likely to provide support for the guideline.

Evaluation of studies

A three-phase approach was used to construct the evi-

dence-based recommendations. The phases included a

systematic literature review of studies in HRS and AKI

in patients with cirrhosis, a comprehensive appraisal of

prior studies, and convening an expert panel to synthe-

size this information and develop consensus based

recommendations. The quality of the overall evidence

and the strength of recommendations were graded using

the Grading of Recommendations Assessment, Develop-

ment and Evaluation system (Table 2) [4-6]. There were

four categories for the quality of overall evidence, ran-ging from A to D. The strength of a recommendation

was determined by the quality of the evidence and was

graded Level 1, 2 or not graded. Recommendations

were Not Graded if they were not based on systematic

evidence and was used to provide guidance where the

topic did not allow adequate application of evidence.

Recommendation statements were developed from the

systematic review, existing guidelines identified in the

supplemental literature review, and expert opinion.

Recommendations were developed by incorporating the

best available evidence and expert opinion. Expert opi-

nion was used when evidence in the literature did not

exist to inform the decision. Recommendation state-

ments were incorporated when they met one of two cri-

teria: if there was strong literature-based evidence or if

the expert panel voted that the recommendation was

appropriate.

Results and discussionI. Evaluation of renal function in patients with cirrhosis

1. Serum creatinine measurements should be used to

evaluate renal function in patients with advanced cirrhosis

until more reliable methods of measuring renal function

become generally available (1D)

Rationale: Serum creatinine (SCr) measurement remainsthe most practical and widely accepted method for esti-

mating renal function in clinical practice in patients

with cirrhosis and is the basis of existing definitions of

AKI. The prognostic impact of renal function in liver

disease is reflected by the inclusion of SCr in the Model

for End-Stage Liver Disease (MELD) score, which is

used to prioritize patients for liver transplantation [9].

However, in cirrhosis, SCr is notoriously inaccurate in

the diagnosis of renal dysfunction as it overestimates

renal function due to decreased creatine production by

the liver, protein calorie malnutrition, and muscle

Table 2 Grading evidence and recommendations (adapted from the GRADE system)

Notes Symbol

Quality of Evidence

High Large, high quality randomized control trials. We are confident that the true effect lies close to that of the estimate of theeffect.

A

Moderate Limited or conflicting data from randomized control trials. The true effect is likely to be close to the estimate of the effect,but there is a possibility that it is substantially different.

B

Low Observational studies or very small randomized control trials. The true effect may be substantially different from theestimate of the effect.

C

Very low Expert opinion. The estimate of effect is very uncertain, and often will be far from the truth. D

Grading Recommendationa

StrongWerecommend

Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, usefuland effective

1

WeakWe suggest

Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of aprocedure or treatment

2

aNot Graded was used to provide guidance where the topic does not allow adequate application of evidence.



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wasting [10-12]. Furthermore, the measurement of SCrusing the Jaffe method can be artificially lowered due to

hyperbilirubinemia [13], or raised by cephalosporins [14]

leading to variability in MELD scores [15]. Serum cysta-

tin C has been suggested as a sensitive marker of renal

function [16-22]; however, recent studies have shown

that like SCr, cystatin C is affected by age, gender, mus-

cle mass and liver disease and overestimates renal func-

tion in patients with cirrhosis [17,23].

Glomerular filtration rate (GFR) is considered the best

estimate of renal function although there is no univer-

sally accepted gold standard for its measurement. Clear-

ance techniques using exogenous markers such as

radiocontrast media, inulin or radioisotopes provide a

more accurate measurement of GFR, but are labor

intensive and expensive and appear to be susceptible to

extra-renal clearance, overestimating GFR by as much as

20 mL/min/1.73 m2

[24,25]. For patients with liver dis-ease, particularly those with advanced cirrhosis, none of

the exogenous clearance markers have been rigorously

studied. When properly performed, timed urinary collec-

tion of creatinine overcomes some of these limitations

[26,27], but due to increased renal tubular creatinine

secretion, creatinine clearance overestimates GFR mea-

sured by inulin clearance by a mean of 13 mL/min/1.73

m2 [27].

2. GFR derived equations should be used cautiously for

assessment of kidney function in cirrhosis since they tend

to overestimate GFR (2D)

Rationale: The Cockcroft Gault [28] and Modified Diet

in Renal Disease (MDRD) [29] equations are widely

used to estimate GFR (eGFR) in the general population

but consistently overestimate GFR in cirrhotic patients.

The Cockcroft Gault equation is heavily influenced by

weight as a reflection of lean body mass, which is not

applicable to cirrhotic patients, in whom edema and

ascites may account for a moderate and in some

patients, even a substantial proportion of their weight

[10,26,30,31]. Several retrospective evaluations of SCr-

based eGFR equations among liver transplant recipients

suggest that the MDRD equations were best able to esti-

mate GFR in comparison to radionucleotide GFR assess-

ment; however, the precision of all GFR equations waspoor [32,33]. Other eGFR equations such as the Chronic

Kidney Disease Epidemiology Collaboration (CKD-EPI)

and cystatin C based eGFR, have been proposed; how-

ever, like the MDRD equations, they have not been vali-

dated in patients with liver disease [34-38]. Therefore,

we encourage very cautious use of these derived equa-

tions for the determination of GFR as they have not

been validated in patients with liver disease.

Recommendations for future research:

Formulate a specific equation for the calculation of

GFR for patients with advanced cirrhosis by iohexol or

inulin GFR determinations along with measurement of

Scr and Cystatin C.

Identify the role of ancillary renal testing such as

diagnostic doppler ultrasound as epidemiological mar-

kers for patients with cirrhosis and renal dysfunction.

Evaluate the value of renal injury biomarkers such as

NGAL (neurtrophil gelatinase-associated lipocalin), IL-

18 and KIM-1 (kidney-injury molecule) in the setting of

AKI within the spectrum of hepatorenal disease.

II. Definition and classification of renal impairment in

cirrhosis

1. Classify AKI in the setting of cirrhosis according to RIFLE

criteria (Not Graded)

Rationale: In 1996, the International Ascites Club (IAC)

proposed a definition and diagnostic criteria for HRS

[39] which was later revised in 2007 (Table 3) [40].

However, the rigid cut off value of SCr of 1.5 mg/dLhas limited prompt management of patients with milder

renal dysfunction. In 2004, the ADQI Workgroup devel-

oped a consensus definition and classification for AKI

known as the RIFLE (Risk, Injury, Failure, Loss, End-

Stage) criteria which stratified acute renal dysfunction

into grades of increasing severity based on changes in

SCr and/or urine output [41]. Subsequently it was recog-

nized that even smaller increases in SCr (absolute

increase in SCr 0.3 mg/dL) are associated with adverse

outcome [42]. As a result, the criteria was modified in

2007 to broaden the definition of AKI (Table 4) [43].

In critically ill patients with cirrhosis, AKI defined by

RIFLE criteria has been shown to be a predictor of hos-

pital survival [44-46]. The final consensus of the work-

group was to apply the RIFLE criteria to define AKI in

patients with cirrhosis irrespective of whether the cause

of the acute deterioration in renal function was related

to a functional or structural disorder (Table 5) [47].

This will certainly identify many patients with AKI with

normal SCr but low GFR and allow us to extend treat-

ment to patients at a lesser level of severity. In addition,

the overall consensus was to also propose that the term

hepatorenal disorders (HRD) be used to describe all

patients with advanced cirrhosis and concurrent kidney

dysfunction (Figure 1). HRD is thus defined as any formof kidney disease occurring in patients with cirrhosis, be

it functional or structural in nature. Such a definition

will allow cirrhotic patients with renal dysfunction to be

properly classified, thereby allowing appropriate studies

to be conducted to define their prognosis and to devise

treatment options.

2. Classify CKD in the setting of cirrhosis according to

Kidney Disease Outcomes Quality Initiatives (K/DOQI) (Not

Graded)

Rationale: As mentioned above, estimation of GFR in

cirrhosis is problematic; therefore, the application of the



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definition of CKD in cirrhosis is challenging. The Work

Group accepted the definition of CKD, as set out by the

practice guidelines from the K/DOQI Work Group [48],

of an eGFR < 60 mL/min/1.73 m2 calculated using the

MDRD-6 formula [29] for more than three months for

patients with cirrhosis (Table 5) [47]. Patients with type-2 HRS who meet these criteria should be considered as

having CKD.

3. Acute on CKD in cirrhosis is defined as a rise in SCr 0.3

mg/dL in less than 48 hours or an increase in SCr 50%

from baseline, or in a patient with cirrhosis whose baseline

GFR has been < 60 ml/min calculated with the MDRD-6

formula for more than three months (Not Graded)

Rationale: It is important to recognize that AKI may

also occur in patients with preexisting HRD. The group

recognizes that acute on CKD does occur in cirrhosis

and has defined it using the RIFLE criteria for AKI and

K/DOQI guidelines for CKD (Table 5) [47].


Multicenter, prospective, epidemiologic (observa-

tional) studies to:

- Investigate the incidence, prevalence, basic demo-

graphics and outcomes of patients with HRD

- Validate new diagnostic criteria of AKI, CKD and

acute on CKD for the cirrhotic population

- Determine whether the development of type-1 HRS

in a patient with pre-existing type-2 HRS is the same

as patients with pre-existing CKD

- Investigate the use of biomarkers to differentiate

between type-1 HRS and other forms of AKI in

patients with cirrhosis.

Table 3 International Ascites Club (IAC) definition and diagnostic criteria for hepatorenal syndrome

1996 Criteria [39]

Major Criteria

Chronic or acute liver disease with advanced hepatic failure and portal hypertension.

Serum creatinine > 1.5 mg/dL or 24-h creatinine clearance of < 40 mL/min.

Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses(repeated vomiting or intense diarrhea) or renal fluid losses

No sustained improvement in renal function defined as a decrease in serum creatinine to < 1.5 mg/dL or increase in creatinine clearance to40 mL/min or more following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline.

Proteinuria < 500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease.

Minor Criteria

Urine volume < 500 mL/d

Urine sodium < 10 mEq/L

Urine osmolality > plasma osmolality

Urine red blood cells < 50 per high power field

2007 Criteria [40]

Cirrhosis with ascites

Serum creatinine > 1.5 mg/dL No improvement of serum creatinine (decrease to a level 1.5 mg/dL) after at least two days of diuretic withdrawal and volume expansionwith albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day

Absence of shock

No current or recent treatment with nephrotoxic drugs

Absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (> 50 red blood cells per high power field),and/or abnormal renal ultrasonography

Table 4 The Acute Dialysis Quality Initiative (ADQI) criteria for the definition and classification of acute kidney injury

(modified RIFLE criteria) [41,43]

AKIStage

Serum creatinine criteria Urine outputcriteria

1 (Risk) Increase Scr 0.3 mg/dL within 48 hours or an increase 150 - 200% (1.5- to 2-fold) from baseline < 0.5 ml/kg/hourfor > 6 hours

2(Injury)

Increase Scr 200% to 299% ( 2- to 3-fold) from baseline < 0.5 ml/kg/hourfor > 12 hours

3(Failure)

Increase Scr 300% ( 3-fold) from baseline or Scr 4.0 mg/dL with an acute increase of 0.5 mg/dL or initiation ofrenal replacement therapy

< 0.3 ml/kg/hourfor 24 hours

or anuria for 12hours

Scr = serum creatinine



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III. Pharmacologic treatment of HRS

1. We suggest using hemodynamic monitoring, when

possible, to help with the management of fluid balance in

patients with HRS (2D)

Rationale: The key management strategy for patients

admitted with cirrhosis is to avoid the development of

HRS by preventing relative renal hypoperfusion, main-

taining an effective circulating volume and renal perfu-sion pressure. Assessment of intravascular volume in

patients with HRS, however, is challenging. Traditional

methods based on clinical examination and static mea-

surements of right atrial and pulmonary artery pressures

are of questionable accuracy in predicting volume

responsiveness and should be used with caution [49-53].

Goal directed therapy with 20% albumin increased cen-

tral blood volume and cardiac index, without subse-

quent changes in central venous pressure [54] as any

fluid bolus which initially expands the intravascular

space, will subsequently expand the third space. Func-

tional hemodynamic monitoring, using continuous cen-

tral venous pressures or indirect measurements of

cardiac indices, should be used when possible to assessthe short term response to a fluid volume bolus [55].

Although pulse pressure variation (PPV) derived from

analysis of the arterial waveform and the stroke volume

variation (SVV) derived from pulse contour analysis are

predictive of fluid responsiveness in patients receiving

volume-controlled mechanical ventilation [51], they are

Table 5 Proposed diagnostic criteria of kidney dysfunction in cirrhosis [47]

Diagnosis Definition

Acute Kidney Injury A rise in Scr 50% from baseline, or a rise Scr > 0.3 mg/dL Type-1 HRS is a specific form of acute kidney injury

Chronic Kidney Disease GFR < 60 ml/min for > 3 month calculated using MDRD-6 formula

Acute on Chronic KidneyDisease

Rise in Scr 50% from baseline or a rise of Scr > 0.3 mg/dL in a patient with cirrhosis whose GFR is < 60 ml/min for> 3 month calculated using MDRD-6 formula

GFR, glomerular filtration rate; HRS, hepatorenal syndrome; Scr, serum creatinine. Both the acute deterioration in renal function and the background chronic renal

dysfunction can be functional or structural in nature. MDRD-6: GFR = 170 Scr (mg/dL) -0.999 x age-0.176 x 1.180 (if black) 0.762 (if female) serum urea

nitrogen-0.170 albumin0.138

Figure 1 Classification of hepatorenal disorder (HRD). Spectrum of hepatorenal disorders in patients with advanced cirrhosis. AKI = acute

kidney injury; CKD = chronic kidney disease; KD = kidney disease; HRS = hepatorenal syndrome. (With permission) 48



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not as reliable in septic patients and those on pressure-

support ventilation [53]. Serial echocardiography can be

used to assess changes in intravascular volume by mea-

suring inferior vena caval diameter, right ventricular

end-diastolic volume index, left ventricular end-diastolic

area index, and the global end-diastolic volume index,

but generally these are not as accurate as using PPV/

SVV, are operator dependent and have not been evalu-

ated in patients with cirrhosis [56,57].

2. We recommend that patients with type-1 HRS be

optimally resuscitated with albumin (initially 1 g of

albumin/kg for two days, up to a maximum of 100 g/day,

followed by 20 to 40 g/day) in combination with a

vasoconstrictor (1A), preferentially terlipressin (2C)

Rationale: The most effective method for treatment of

type-1 HRS currently available is the administration of

systemic vasoconstrictor drugs (Table 6) in order to

reduce the marked vasodilatation in the splanchnic andsystemic circulations thereby improving the associated

impaired circulatory function [58,59]. Although rando-

mized controlled trials [60-77] and meta-analysis [78,79]

of the combination of terlipressin and albumin have

been shown to reverse HRS type 1 and improve renal

function in patients with type-1 HRS (Figure 2), data

regarding survival benefit has been limited although it

may allow survival to transplantation (Figure 3). Ther-

apy should be discontinued after four days in non-

responders and only continued thereafter in partial

responders (SCr improves, but does not decrease to 70 mmHg

Noradrenaline [69,77,80] 0.5 to 3.0 mg/hour (continuous infusion). Titrate to achieve a 10 mmHg increase in MAP

Midodrine + Octreotide[82-87]

Midodrine: 7.5 to 12.5 mg orally three times. Titrate to achieve a 15 mm Hg increase in MAP from baselineOctreotide:100 to 200 g subcutaneously three times daily or 25 g bolus, followed by intravenous infusion of 25 g/

hour

MAP: mean arterial pressure



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Adsorbent Recirculating System (MARS) is now commer-

cially available in the US and Europe. Although MARS

therapy has not demonstrated a definite survival benefit in

patients with liver disease, it has been shown to improve

hepatic encephalopathy (Figures 4, 5) [125-131]. Cell-

based systems aim to provide the excretory, synthetic, and

metabolic functions of the liver using living liver cells. In

addition to detoxification, cell-based systems can also pro-

vide some synthetic and regulatory functions; however,

they have mainly been tested in single-center phase I and

II trials, and none have yet received US Food and Drug

Administration (FDA) approval.

Figure 2 Forest plot of meta-analysis on terlipressin plus albumin for patients with hepatorenal syndrome. The outcome measure is

reversal of hepatorenal syndrome.

Figure 3 Forest plot of meta-analysis on terlipressin plus albumin for patients with hepatorenal syndrome. The outcome measure is

survival.



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Further observational studies and ultimately rando-

mized controlled trials directed to the identification of the

appropriate indications, timing of intervention, and cost

effectiveness of supportive detoxification therapies. Conse-

quently, the most appropriate outcome for studies would

be short-term survival as a bridge to transplantation.

V. Interventional and surgical management of HRS

1. We recommend use of a transjugular intrahepatic

portosystemic shunt (TIPS) as a treatment option for

patients with type-2 HRS with refractory ascites who require

large-volume paracentesis (1C)

Rationale: Very few studies have assessed the role ofTIPS in patients with HRS (Table 8) [135-13 8]. In

patients with type-2 HRS, TIPS has been shown to

improve refractory ascites and improve renal function

without improvement in survival [138]. However, new

hepatic encephalopathy, deterioration of previous hepa-

tic encephalopathy [136] or mild and transient dete-

rioration of liver function tests [137] has been reported

following TIPS. In patients with type-1 HRS, TIPS may

improve renal function and survival [136,137]; however,

there is insufficient data to support the use of TIPS as a

first-line treatment of patients with type-1 HRS. TIPS isnot recommended in patients with severe liver failure

defined as serum bilirubin > 5 mg/dl, INR > 2 or Child-

Pugh score > 11, hepatic encephalopathy or severe car-

diopulmonary diseases.

2. We suggest liver transplantation alone for candidates

with type-1 HRS for less than four weeks and simultaneous

liver-kidney (SLK) for those at risk for non-recovery of renal

function (2D)

Rationale: As the waiting time for liver transplantation

has increased, the incidence of pre-transplant renal dys-

function and RRT has also increased. In patients with

renal dysfunction at the time of liver transplantation

(LT), it is important to know whether renal functionwill improve, stabilize or continue to progress following

transplantation. However, the level and duration of

renal dysfunction, including RRT, beyond which renal

recovery is not possible following LT alone is unknown.

Several investigators have studied the impact of pre-

transplant AKI on post transplant outcomes; however,

the small study sample size, retrospective design, report-

ing bias, and variation in definitions used to define renal

dysfunction hinders comparison between these studies

[139-145].

Table 7 Extracorporeal liver support system

Technique

Artificial (Non-cell based)

Hemoperfusion [96-101] Removal of protein-bound toxins by circulating blood over a sorbent mater ial

Hemodiabsorption [102-105] Hybrid process in which blood is passed through a hemodialyzer containing a suspension of sorbentmaterial, such as charcoal or resin, in the extracapillary space

Plasma Exchange [106-109] Exchange of plasma volume

Plasmapheresis [110] Plasma is separated from the cellular blood components and replaced with normal plasmaconstituents, allowing the removal of circulating toxins and waste products.

Plasma Filtration [111-117] Removes a specific plasma fraction containing substances within a specific molecular weight.

Albumin dialysis Albumin containing dialysate using an anion exchange resin and active charcoal adsorption allowingalbumin-bound toxins in the blood to cross the membrane and bind to the albumin. Water solubletoxins are dialyzed from the albumin circuit by a standard hemodialysis or continuous renalreplacement therapy (CRRT) machine.

Single Pass Albumin Dialysis (SPAD)118-121]

Prometheus [122-124]

Molecular Adsorbent RecirculatingSystem (MARS) [125-131]

Bioartificial (Cell-based) [132-134]

Porcine

HepatAssist Bioartificial Liver Support System (BLSS) Modular Extracorporeal Liver Support(MELS) Hybrid-Bioartificial Liver (HBAL) Radial Flow Bioreactor (RFB) TECA-Hybrid Artificial Liver Support System AMC-Bioartificial Liver

Human

Extracorporeal Liver Assist Device (ELAD)



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Currently there are no standard criteria for the evalua-

tion, selection and/or allocation of a kidney at the time

of LT. Despite an increase in the rate of SLK transplan-

tation immediately following the implementation of the

MELD allocation system in March 2002 (Figure 6),

recent Organ Procurement and Transplantation Net-

work (OPTN) data suggest a decrease since 2007 which

may be due to consensus guidelines published at that

time [146,147]. Based on the published consensus guide-

lines, the OPTN Liver and Intestine Committee andKidney Committee recently developed proposed listing

criteria for SLK candidate selection and allocation (Pol-

icy 3.5.10) (Table 9).

The duration of pre-liver transplant kidney dysfunc-

tion or dialysis that is amenable to recovery is not

known. Retrospective studies from single centers have

shown the importance of the duration of > 12 weeks of

SCr 1.5 mg/dL and dialysis 4 weeks pre-transplant

on post transplant renal outcomes [140,143-145]. How-

ever, the renal outcome of patients dialyzed for > 4

weeks is unknown as many of these patients frequently

undergo SLK. Timing of dialysis is related to numerous

factors and is a complex process. Since a threshold ofdialysis duration that is sufficiently predictive of renal

recovery has not been established, and also because

initiation of dialysis is physician/center dependent,

Figure 4 Forest plot of meta-analysis on Molecular Adsorbent Recirculating System (MARS) for patients with hepatorenal syndrome.

The outcome measure is improvement of hepatic encephalopathy.

Figure 5 Forest plot of meta-analysis on Molecular Adsorbent Recirculating System (MARS) for patients with hepatorenal syndrome.

The outcome measure is survival.



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dialysis duration as a criterion for SLK should be used

with caution in patients who do not have end-stage

renal disease. The decision for SLK versus LT alone

should be undertaken with consideration of duration of

HRS, AKI and CKD and risk factors for progression of

CKD present at the time of liver transplant such as

hypertension, diabetes and obesity. Currently there are

several pitfalls with the SLK guidelines such as defini-

tion of AKI, GFR determination, timing of initiation of

dialysis and duration of dialysis. To that end, the ADQI

group unanimously agreed that using the existing litera-

ture is not sufficient to allow guidelines or criteria to be

set.


Multicenter, prospective, observational studies in

patients undergoing SLK to determine:

- The predictive value of RIFLE classifications pre-

transplant on post liver transplant outcomes

- Which RIFLE class and for what duration of AKI

pre-transplant is associated with rates of renal recov-

ery that warrant SLK

- What is the recovery rate of native kidney function

in patients with pre-transplant type-1 or 2 HRS

Epidemiologic studies that document long-term

Table 8 Clinical trials on transjugular intrahepatic portosystemic shunt (TIPS) in patients with hepatorenal syndrome

Author Year N Type of Study Study Population(n)

Pre-TIPS Cr Post-TIPS cr Survival

Brensing[135]

1997 16 P rospectiveuncontrolled

HRS Type 1 & 2 2.57 1.59 mg/ dl

1.18 0.59 mg/dl

56%

Guevara[136]

1998 7 Prospectiveuncontrolled

HRS Type 1 5.0 0.8 mg/dl 1.8 0.4 mg/dl 28%Mean survival: 140 68

days

Brensing[137]

2000 41 Prospective Non-TIPS (n = 10)HRS Type 1 (n= 7)

HRS Type 2 (n = 3)

2.3 1.7 mg/dl 1.5 1.2 mg/dl Mean Survival:TIPS: 92 16 weeks

Non TIPS: 12 8.5 weeks

TIPS (n = 31)HRS Type 1 (n = 14)HRS Type 2 (n = 17)

3 month survivalTIPS: 81%

Non TIPS:10%

Testino [138] 2003 18 Prospectiveuncontrolled

HRS Type 2 (n = 18) 1.9 0.5 mg/dl 0.9 0.3 mg/dl 67%: Transplanted

Figure 6 Percent of Adult Simultaneous Liver-Kidney (SLK) Transplant Amongst all Cadaveric Liver Transplant Recipients (1999-2009).



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patient and renal outcomes and the prognostic factors

for these outcomes in patients with HRS who receive

LT alone, who recover residual renal function, remain

on dialysis and those subsequently receiving renal

transplantation.

ConclusionsSince first defined in 1996 by the IAC, there has been

substantial progress towards understanding the patho-

genesis and natural history of HRS. However, there

remains a significant deficiency in our knowledge

regarding its management. The IAC has set out clear

diagnostic criteria for both acute and chronic forms of

HRS, but has not delineated guidelines for the diagnosis

of other forms of renal impairment in cirrhosis, be they

acute or chronic. Well-accepted definitions and staging

systems for CKD and AKI exist, but have not been con-sistently applied to patients with advanced liver disease.

Indeed, it must be understood that although our recom-

mendations are based, to the best extent possible, on

data, there are insufficient data to guide many important

decisions. In addition, although our Work Group

included a wide range of specialists from around the

world, we do recognize that there exists regional hetero-

geneity in practice. As a result, our findings should be

considered a first step in the process of standardization

of the definition of AKI in patients with cirrhosis. Once

agreed, these new diagnostic criteria of AKI for cirrhosis

will need to be validated and the threshold for the diag-

nosis of type-1 HRS may need to be revised to a lowertarget value to allow patients with a lesser degree of SCrrise to receive prompt appropriate treatment. In addi-

tion, criteria for SLK may need to be revisited in lieu of

the new classification and to determine whether the new

classification and definition will improve patient out-

comes. One clear conclusion of this ADQI meeting is

that multicenter, prospective, long-term outcome studies

in patients with advanced cirrhosis and HRS are

urgently needed.

Key messages The ADQI Work Group recommends incorpora-

tion of the modified RIFLE criteria to define AKI in

patients with cirrhosis irrespective of whether the

cause of the acute deterioration in renal function isrelated to a functional or structural discorder.

Regarding the current state of combined liver-kid-

ney transplantation in patients with cirrhosis and

kidney disease, including HRS, the ADQI group

unanimously agreed that using the existing literature

is not sufficient to allow guidelines or criteria to be

set.

Multicenter prospective, long-term outcome stu-

dies in patients with advanced cirrhosis and HRS are

urgently needed.

Abbreviations

ADQI: Acute Dialysis Quality Initiative; AKI: acute kidney injury; CKD: chronic

kidney disease; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration;CRRT: continuous renal replacement therapy; eGFR: estimated glomerular

filtration rate; FDA: Food and Drug Administration; GFR: glomerular filtration

rate; HRD: hepatorenal disorders; HRS: hepatorenal syndrome; IAC:

International Ascites Club; IL: interleukin; KIM-1: kidney-injury molecule 1; K/

DOQI: Kidney Disease Outcomes Quality Initiatives; LT: liver transplantation;

MARS: molecular adsorbent recirculating system; MDRD: Modified Diet in

Renal Disease; MELD: Model for End-Stage Liver Disease; NGAL: neurtrophil

gelatinase-associated lipocalin; OPTN: Organ Procurement and

Transplantation Net work; PPV: pulse pressure variation; RIFLE: risk: injury:

failure: loss: end-stage; RRT: renal replacement therapy; Scr: serum creatinine;

SLK: simultaneous liver-kidney; SVV: stroke volume variation; TIPS: transjugular

intrahepatic portosystemic shunt.

AcknowledgementsThe authors wish to acknowledge the University of Southern California for

organization of ADQI 8th International Consensus Conference. This

conference was supported by unrestricted educational grants from Ikaria,

Gambro Renal Care, Otsuka Pharmaceutical, Nx-Stage Medical, IV League Inc.,

and Baxter Inc. The authors would also like to acknowledge all the

participants of the 8th ADQI meeting: Jawad Ahmad, MD (Mount Sinai

Hospital, USA), Ali Al-Khafaji, MD (University of Pittsburgh School of

Medicine, USA), Paolo Angeli, MD (University of Padova, Italy), Rinaldo

Bellomo, MD (Monash University, Australia), Pat Brophy, MD (University of

Iowa, USA), Jorge Cerda, MD (Albany Medical College, USA), Lakhmir S.

Chawla, MD (George Washington Medical Center, USA), Andrew Davenport,

MD (University College London Medical School, UK), Connie Davis, MD

(University of Washington, USA), Yuri S. Genyk, MD (University of Southern

Table 9 Criteria for simultaneous liver-kidney transplant candidates as proposed by the UNOS Kidney Transplantation

Committee and the Liver and Intestinal Organ Transplantation Committee (UNOS Policy 3)

a. Chronic kidney disease (CKD) requiring dialysis with documentation of the CMS form 2728 a

b. Chronic kidney disease (GFR < = 30 ml/min by MDRD6 or iothalamate measurement and proteinuria > 3 gms/day with 24 hour proteinmeasurement or urine protein/creatinine ratio > 3 not requiring dialysis

c. Sustained acute kidney injury requiring dialysis for 6 weeks or more (defined as dialysis at least twice per week for 6 consecutive weeks)

d. Sustained acute kidney injury (GFR < = 25 ml/min for 6 weeks or more by MDRD6 or direct measurement) not requiring dialysis

e. Sustained acute kidney injury: Patients may also qualify for SLK listing with a combination of time in categories (c) and (d) above for a total of sixweeks (or example, patients with a GFR < 25 ml/min for 3 weeks followed by dialysis for 3 weeks).

f. Metabolic Disease

CKD, chronic kidney disease; CMS, Center for Medicare & Medicaid Services; GFR, glomerular filtration rate; MDRD-6, Modification of Diet in Renal Disease formula

calculated using 6 variables of serum creatinine, serum urea, serum albumin, age, gender and whether the patient is African-American or not.aCMS form 2728: Form required by Medicare & Medicaid stating that a dialysis patient has end-stage renal disease with no chance of renal recovery



Page 12 of 17


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California, USA), Noel Gibney, MD (University of Alberta, Canada), John A.Kellum, MD (University of Pittsburgh School of Medicine, USA), Mitra K.

Nadim, MD (University of Southern California, USA), Neesh Pannu, MD

(University of Alberta, Canada), Francesco Salerno, MD (University of Milan,

Italy), Randall Sung, MD (University of Michigan, USA), Khajohn

Tiranathanagul, MD (Chulalongkorn University, Thailand), (Ashita Tolwani,

MD, University of Alabama, USA), Florence Wong, MD (University of Toronto,Canada).

Author details1Department of Medicine, University of Southern California, 1520 San Pablo

Street, Suite 4300, Los Angeles, CA, 90033 USA. 2Department of Critical CareMedicine, University of Pittsburgh, Room 608, Scaife Hall, 3550 Terrace Street,

Pittsburgh, PA 15261 USA. 3Department of Medicine, University College

London Medical School, Rowland Hill Street, London NW3 2PF UK.4Department of Medicine, University of Toronto, 9th Floor Rm. 9N983, 200

Elizabeth Street, Toronto, ON M5G 2C4 Canada. 5Department of Medicine,

University of Washington, Box 356174, 1959 NE Pacific Street, Seattle, WA

98195, USA. 6Department of Medicine, University of Alberta, 11-107 csb 8440

112 Street, Edmonton, Canada T6G 2G3, AB, Canada. 7Department of

Medicine, University of Alabama, ZRB 605, 1530 3rd Ave. S, Birmingham, AL

35294-0007 USA. 8Australian and New Zealand Intensive Care Research

Centre, School of Public Health and Preventive Medicine, Monash University,

Alfred Centre, Commercial Rd, Prahran, Melbourne, Victoria 3181, Australia.9Department of Surgery, University of Southern California, 1510 San PabloStreet, Suite 200, Los Angeles, CA, 90033 USA.

Authors contributionsMKN, JAK and YSG were the main organizers of this meeting and helped to

draft the manuscript. AD, CD, NP, RB, FW and AT were the facilitators for

each Work Group and participated in drafting the sections that were related

to their Work Group. All authors read and approved the final manuscript.

Competing interests

ADQI is supported by a group of sponsors and no funding is accepted for

the development of specific guidelines and every effort is made by to avoid

any actual or perceived conflicts of interest that may arise as a result of an

outside relationship of a member of the ADQI Work Group. Prior to the

meeting, all members of the Work Group are required to complete, sign and

submit a disclosure and attestation form showing all their relationships thatmight be actual or perceived conflicts of interest. None of the companies

that provided financial support for this meeting were involved in any way in

the organization of the meeting, the decision regarding invited faculty, thedesign and contents of the meeting, the collection, management, analysis,

and interpretation of the data, and preparation, review, or approval of the

manuscript. MKN has served as an advisor for Ikaria and has also served as aspeaker for Gambro. JAK has served as a consultant and has received grant

support from Gambro and Baxter. AT, JC and NG have served as speakers for

Gambro. CD has served as an advisor for Ikaria. The other 13 members of

the Work Group reported no relevant financial relationships.

Received: 8 November 2011 Revised: 30 December 2011

Accepted: 9 February 2012 Published: 9 February 2012

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